The present invention is directed to a process for the preparation of baccatin III, taxol, docetaxel and their analogs from borneol (1) and camphor (2), commonly known articles of commerce.
Processes for the total synthesis of taxol and other tetracyclic taxanes from commodity chemicals have been proposed. For example, in U.S. Pat. No. 5,405,972, Holton et al. disclose a process for the synthesis of taxol and other tetracyclic taxanes from xcex2-patchouline epoxide which, in turn, may be obtained from borneol (1) and camphor (2). Yields obtained by these processes, however, leave some room for improvement.
Leriverend and Conia (Bull. Soc. Chim. Fr., 1970, 1060) observed that diol 4 (which is readily prepared from either camphor or borneol) when heated to 220xc2x0 C. for a period of one hour rearranged to provide a mixture of ketones 5 and 6 in a ratio of 1:2. Ketone 5 is of great utility in the synthesis of taxanes.
The preparation of diol 4 and ketones 5 and 6 is illustrated in Reaction Scheme 1. 
Briefly, therefore, the present invention is directed to a process for the preparation of ketone 5 in relatively high yield and without contamination with ketone 6. The process comprises treating a compound having the formula: 
with a base and a silylating agent to form a compound having the formula: 
The present invention is further directed to a process for converting ketone 5 into taxol, docetaxel, and other taxanes. According to this process, a derivative of ketone 5 having the formula: 
is treated with an alkyl metal species, preferably tert-butyllithium, or is treated with a Lewis acid, preferably TMSOTf, in the presence of a tertiary amine base, preferably triethylamine, to form a compound having the formula: 
wherein P2 is hydrogen or a hydroxyl protecting group. The process for converting ketone 5 into taxol, docetaxel, and other taxanes may additionally comprise treating a compound having the formula: 
with a Lewis acid, preferable TMSOTf, in the presence of a tertiary amine base, preferably triethyl amine, to form a compound having the formula: 
wherein P2 and P10 are independently hydrogen or a hydroxyl protecting group.
The present invention is additionally directed to the following intermediates having the formulae 
wherein P2, P9, P10 and P13 are independently selected from hydrogen and hydroxy protecting groups. Compounds containing one or more hydroxy protecting groups can be converted to their hydroxy group analogs by removing such hydroxy protecting groups using standard methods. The compounds identified above are key intermediates in the synthesis of baccatin III, 1-deoxy baccatin III, taxol, 1-deoxy taxol, docetaxel, 1-deoxy docetaxel, and the analogs of these compounds.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
The present invention provides a process for the preparation of ketone 5 in high yield relative to its isomer 6. When diol 4 is treated with a base in the presence of a silylating agent, ketone 5 can be obtained in greater than 95% yield. The base employed is preferably stronger than an alkoxide base. More preferably, the base is a hydride base or an amide base. Still more preferably, the base is potassium hydride or potassium hexamethyldisilazide. The base is preferably nonreactive with the silylating agent selected for the reaction.
Silylating agents for the reaction include those compounds comprising the group xe2x80x94SiR1R2R3 wherein R1, R2 and R3 are independently substituted or unsubstituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, monocyclic aryl or monocyclic heteroaryl. Such silylating agents may further comprise a hydride or triflate group, for example tri(hydrocarbyl)silyl halides and tri(hydrocarbyl)silyl triflates. The hydrocarbon moieties of these silylating agents may be substituted or unsubstituted and preferably are substituted or unsubstituted alkyl or aryl. Trialkylsilyl halides are more preferred with alkyl groups containing from one to four carbon atoms. Still more preferably, the silylating agent is triethylsilyl chloride. Ethereal solvents are preferred for the reaction, with THF being the more preferred solvent.
While the temperature at which the reaction is carried out is not narrowly critical, the temperature may affect the overall yield of the reaction. Preferably, the temperature of the reaction is maintained below about 50xc2x0 C.; more preferably, the temperature is maintained at or below about 25xc2x0 C.; even more preferably, the temperature initially is maintained at or below about 0xc2x0 C. and subsequently is maintained at or below about 25xc2x0 C. As illustrated in the Examples, these latter conditions produced ketone 5 in 96% yield.
Likewise, the sequence of addition of diol 4, the base and the silylating agent is flexible. For example, diol 4, the base and the silylating agent may be combined at the beginning of the process and reacted in essentially a single step, or these reagents may be combined as described in the Examples.
The reagents for the foregoing reaction (as well as the reagents for the reactions subsequently discussed in this application) are preferably provided in approximately stoichiometric amounts, although various ratios of the reagents can be effectively employed.
Without being bound to any specific theory, it is believed based upon the evidence to date that the base operates to deprotonate the two hydroxy groups of diol 4. The less-sterically-hindered deprotonated hydroxy group (which corresponds to the front hydroxy group of the structure of diol 4 illustrated in Reaction Scheme 1) then reacts with the silylating agent to form a protected hydroxy group. The other deprotonated hydroxy group (which corresponds to the rear hydroxy group of the structure of diol 4 illustrated in Reaction Scheme 1) does not react with the silylating agent. The protected diol 4 then undergoes the oxy-Cope rearrangement to provide a nine-membered ring containing a silyl enol ether and an enolate. Upon the addition of water the enolate is protonated and the subsequent aldol condensation is directed by the position of the silyl enol ether to provide ketone 5.
Ketone 5 can be further converted to other useful taxane synthetic intermediates as shown below.
As shown in reaction scheme 2, treatment of ketone 5 with an amide base, preferably an alkali metal amide base and more preferably LHMDS, in an ethereal solvent, preferably THF, and then with a hydroxylating agent, preferably an oxaziridine and more preferably phenylsulfonyl oxaziridine, provides allylic alcohol 7. Allylic alcohol 7 in the presence of an epoxidizing agent, preferably a peroxy acid and more preferably m-chloroperbenzoic acid, is converted to epoxide 8. Epoxide 8 can be reduced stereoselectively to diol 9 (P2=H), using a hydride reducing agent, preferably a borohydride and more preferably sodium borohydride. The secondary hydroxyl group of 9 can be protected with any of a variety of protecting groups, using standard methods for their attachment. Treatment of 9 with a Lewis acid in the presence of a tertiary amine base, preferably triethyl amine, causes its rearrangement to give 10. In general, the Lewis acids that can be used include triflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthanides, and actinides (American Chemical Society format), with a preferred Lewis acid being TMSOTf. The second secondary hydroxyl group of 10 can be protected with any of a variety of protecting groups so that P10 and P2 may be the same or different and readily chemically distinguishable from each other. 
Alternatively, as shown in reaction scheme 3, treatment of ketone 5 with a hydride reducing agent, preferably a borohydride and more preferably sodium borohydride, in the presence of a Lewis acid, preferably a lanthanide metal halide or triflate and more preferably a samarium or cerium halide, selectively furnishes allylic alcohol 11, which undergoes epoxidation from the xcex1-face in the presence of peracids such as m-chloroperbenzoic acid (or hydroperoxides such as tert-butyl hydroperoxide in the presence of metal catalysts or promoters such as titanium (+4) or vanadium (+5) to give epoxide 12 (P2=H). The secondary hydroxyl group of 12 can be protected with any of a variety of protecting groups, using standard methods for their attachment. The epoxide ring of 12 can be opened to provide allylic alcohol 13, using either an alkyl metal species, preferably an alkyllithium and more preferably tert-butyllithium, or a Lewis acid, in the presence of a tertiary amine base, preferably triethylamine. In general the Lewis acids that can be used include triflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthanides, and actinides (American Chemical Society format), with a preferred Lewis acid being TMSOTf. Allylic alcohol 13 again undergoes epoxidation from the xcex1-face in the presence of peracids such a m-chloroperbenzoic acid (or hydroperoxides such as tert-butyl hydroperoxide in the presence of metal catalysts or promoters such as titanium (+4) and vanadium (+5)) to give epoxide 14. Treatment of 14 with a Lewis acid in the presence of a tertiary amine base, preferably triethyl amine, causes its rearrangement to give 15. In general the Lewis acids that can be used include triflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthanides, and actinides (American Chemical Society format), with a preferred Lewis acid being TMSOTf. The second secondary hydroxyl group of 15 can be protected with any of a variety of protecting groups so that P10 and P2 may be the same or different and readily chemically distinguishable from each other.
It should be noted that 15 is the C(2) epimer of 10. 
Alcohols 10 and 15 undergo the xe2x80x9cepoxy alcohol fragmentationxe2x80x9d to provide 16 and 17, respectively (P13=H), which possess the taxane AB ring structure. The epoxy alcohol fragmentation is carried out by first treating the substrate with an epoxidizing agent, then warming the product in the presence of a metal salt. The epoxidizing agent preferably is a peroxy acid such as m-chloroperbenzoic acid (or a hydroperoxide such as tert-butyl hydroperoxide in the presence of metal catalysts or promoters such as titanium (+4) or vanadium (+5)). The preferred metal salt is a halide or alkoxide of a group IA, IIA, IIIB, IVB, VB, VIB, VIIB or VIII metal, with a preferred metal salt being titanium tetraisopropoxide. More preferably, the epoxidizing agent is tert-butyl hydroperoxide in the presence of titanium tetraisoprepoxide. The C(13) secondary hydroxyl group of 16 and 17 can be protected with any of a variety of protecting groups so that P13, P10 and P2 may be the same or different and readily chemically distinguishable from each other. 
Treatment of 17 (P2, P10, and P13=hydroxyl protecting groups) with a potassium base and methyl iodide provides 18, having the xcex2 configuration of the newly introduced methyl group, as shown in reaction scheme 4. The preferred potassium base is potassium hexamethyldisilazide, the preferred solvent is tetrahydrofuran, and the preferred temperature is xe2x88x925xc2x0 C. to 0xc2x0 C. Treatment of 18 (P2, P10, and P13=hydroxyl protecting groups) with a base followed by 4-pentenal provides 19 (P2, P10, P13=hydroxyl protecting groups and P7=H). Preferred bases are chosen from lithium and magnesium amides with bromomagnesium diisopropyl amide (BMDA) being a more preferred base. The preferred solvent is tetrahydrofuran and the preferred temperature is between xe2x88x9245xc2x0 C. and 0xc2x0 C. The C7 hydroxyl group of 19 can be protected with a variety of hydroxyl protecting groups. For example, treatment of 19 with phosgene and pyridine then ethanol, followed by selective removal of P2, provides an intermediate (19, P2=H, P7=CO2Et, P10=TES, and P13=TBS) used in the total synthesis of baccatin III and taxol (See, e.g., J. Amer. Chem. Soc., 1994, 116, 1597-1600). 
Also, oxidation of 10 (P10=H) and 15 (P10=H) with any of a variety of standard oxidizing agents provides, respectively, 21 and 20, shown in reaction scheme 5. Preferred oxidizing agents are chromium based reagents. Pyridinium dichromate is a particularly preferred oxidizing agent. Reduction of 21 and 20 with hydride reducing agents provides 23 (P10=H) and 22 (P10=H), respectively. Preferred reducing agents are chosen from the group of borohydrides and aluminohydrides with lithium aluminum hydride being a more preferred reducing agent. The newly introduced secondary hydroxyl group of 23 (P10=H) and 22 (P10=H) can be protected with any of a variety of protecting groups so that P10 and P2 may be the same or different and readily chemically distinguishable from each other. Alcohols 23 and 22 undergo the xe2x80x9cepoxy alcohol fragmentationxe2x80x9d to provide 25 and 24 respectively (P13=H), which possesses the taxane AB ring structure.
The C(13) secondary hydroxyl group of 24 and 25 can be protected with any of a variety of protecting groups so that P13, P10 and P2 may be the same or different and readily chemically distinguishable from each other. 
Ketone 20 may be further oxidized to provide a more advanced taxane synthetic intermediate, as shown in reaction scheme 6. Treatment of 20 with an amide base and a tri(hydrocarbon)silyl halide or triflate provides an intermediate silyl enol ether, which is treated directly with a peracid to give 26 (P9=H). The preferred amide base is an alkali metal amide base and more preferably is LDA. The preferred tri(hydrocarbon)silyl halide or triflate is a trialkylsilyl chloride with triethyl silyl chloride being particularly preferred. The preferred peracid may include peroxy carboxylic acids with m-chloroperbenzoic acid being particularly preferred. The C(9) secondary hydroxyl group of 26 can be protected with any of a variety of protecting groups so that P9, P10 and P2 may be the same or different and readily chemically distinguishable from each other. Reduction of 26 with hydride reducing agents provides 27 (P10=H). Preferred reducing agents are chosen from the group of borohydrides and aluminohydrides; the most preferred reducing agent is lithium aluminum hydride. The newly introduced secondary hydroxyl group of 27 (P10=H) can be protected with any of a variety of protecting groups so that P10, P9 and P2 may be the same or different and readily chemically distinguishable from each other. Alcohol 27 undergoes the xe2x80x9cepoxy alcohol fragmentationxe2x80x9d to provide 28 (P13=H), having the taxane AB ring structure. The C(13) secondary hydroxyl group of 2 can be protected with any of a variety of protecting groups so that P13, P10, P9 and P2 are the same or different and readily chemically distinguishable from each other. Treatment of 28 with an amide base, preferably an alkali metal amide base and more preferably LHMDS, and a methyl halide or sulfonate, preferably methyl iodide, in an ethereal solvent, preferably THF, provides 29, which has been used as an intermediate in the total synthesis of C(1) deoxy baccatin III (See, e.g., PCT Patent Application Serial No. PCT/US97/07569, International Publication No. WO 97/42181). 
Definitions
As used herein, the term xe2x80x9cLHMDSxe2x80x9d means lithium hexamethyldisilazide; xe2x80x9cKHMDSxe2x80x9d means potassium hexamethyldisilazide; xe2x80x9cLDAxe2x80x9d means lithium diisopropyl amide; xe2x80x9cBMDAxe2x80x9d means bromomagnesium diisopropyl amide; xe2x80x9cPSOxe2x80x9d means phenylsulfonyl oxaziridine; xe2x80x9cTHFxe2x80x9d means tetrahydrofuran; xe2x80x9cmCPBAxe2x80x9d means meta-chloroperbenzoic acid; xe2x80x9cTESxe2x80x9d means triethylsilyl; xe2x80x9cTMSxe2x80x9d means trimethylsilyl; xe2x80x9cTfxe2x80x9d means xe2x80x94SO2CF3; xe2x80x9cTEAxe2x80x9d means triethylamine; xe2x80x9ct-BuLixe2x80x9d means tert-butyllithium; xe2x80x9cPDCxe2x80x9d means pyridinium dichromate; xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride; xe2x80x9cTBHPxe2x80x9d means tert-butyl hydroperoxide; xe2x80x9cTTIPxe2x80x9d means titanium tetraisoprepoxide; xe2x80x9cprotected hydroxyxe2x80x9d means xe2x80x94OP wherein P is a hydroxy protecting group; and xe2x80x9chydroxy protecting groupxe2x80x9d includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other hydroxyl, protecting groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981, and Second Edition, 1991.
The xe2x80x9chydrocarbonxe2x80x9d moities described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
The alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbon radicals or hetero-substituted with the various substituents defined herein.
The aryl moieties described herein contain from 6 to 20 carbon atoms and include phenyl. They may be hydro-carbon or heterosubstituted with the various substituents defined herein. Phenyl is the more preferred aryl.
The heteroaryl moieties described are heterocyclic compounds or radicals which are analogous to aromatic compounds or radicals and which contain a total of 5 to 20 atoms, usually 5 or 6 ring atoms, and at least one atom other than carbon, such as furyl, thienyl, pyridyl and the like. The heteroaryl moieties may be substituted with hydrocarbon, heterosubstituted hydrocarbon or hetero-atom containing substituents with the hetero-atoms being selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; amino; and amido.
The heterosubstituted hydrocarbon moieties described herein are hydrocarbon moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; amino; and amido.
The acyl moieties described herein contain hydrocarbon, substituted hydrocarbon or heteroaryl moieties.
The alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon moieties.